ABSTRACT This supplement was written in response to the original NOT-AI-20-031: Notice of Special Interest (NOSI): Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19), and submitted under PA-18-591]. COVID19, caused by the betacoronavirus (CoV) clade SARS-CoV-2, ranges from asymptomatic disease to fatal multi-organ failure. Both innate and T cell-mediated adaptive immunity are important for limiting viral replication. Nevertheless, hyperactivation of the immune response in patients with more severe disease may precipitate a ?cytokine storm? that results in aggravated morbidity and high mortality. Relevant to the role of immune hyperactivation in COVID disease pathogenesis are our recent studies on asthmatic inflammation showing how allergens and air pollution particulate matter (PM) overcome immune tolerance mechanisms operating in the airway to license tissue inflammation. We identified the JAG1-NOTCH4 axis as a key pathogenic mechanism activated by the allergens and PM that acts as a molecular switch to break down immune tolerance in the lung and consequently promote inflammation. Along this mechanism we identified that NOTCH4 was selectively induced on lung Treg cells in an allergen and interleukin-6 (IL-6)-dependent manner, and it directed their subversion into Th2/Th17 effector-like T cells. Importantly, our preliminary results reveal that NOTCH4 expression is upregulated on circulating Treg cells of COVID19 subjects as a function of disease severity, thus implicating this mechanism in disease pathogenesis in COVID19 subjects. Our central hypothesis is that dysregulation of innate and adaptive immunity in COVID19 involves the subversion of Treg cells in an IL-6 and NOTCH4-dependent manner. Our study team is composed of a multidisciplinary group of R01-funded investigators with prior collaborative work, clinical expertise in the care of critically ill COVID19 patients, and research expertise in the role of Treg cells in immunological tolerance. We propose to profile the innate and adaptive immune responses in subjects with mild-moderate and severe COVID19 disease as compared to convalescent and healthy control subjects. We will correlate these changes with NOTCH4 expression on circulating Treg cells and the latter?s immune regulatory functions. We will also examine the impact of Notch4 expression on transcriptional alterations in Treg and T effector cells in patients with COVID-19. Our studies offer a mechanistic approach to the elucidation of the enigma of immune hyperactivation in COVID19 and the promise to identify targets for precision therapy in this disease.